CN101163474B - Drug for curing corneal and conjunctival disease - Google Patents

Drug for curing corneal and conjunctival disease Download PDF

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Publication number
CN101163474B
CN101163474B CN2006800132466A CN200680013246A CN101163474B CN 101163474 B CN101163474 B CN 101163474B CN 2006800132466 A CN2006800132466 A CN 2006800132466A CN 200680013246 A CN200680013246 A CN 200680013246A CN 101163474 B CN101163474 B CN 101163474B
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methyl
tetrazolium
biphenyl
corneal
carboxylic acid
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CN101163474A (en
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柴垣圭一
平井慎一郎
中村雅胤
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Santen Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

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Abstract

The purpose of the invention is to provide a therapeutic agent for a corneal/conjunctival disorder. A compound represented by the general formula (1) or a salt thereof shows an excellent ameliorating effect in a corneal disorder model, and therefore is useful as a therapeutic agent for a corneal/conjunctival disorder such as dry eye, corneal ulcer, keratitis and conjunctivitis. In the general formula, the ring Y represents a substituted or unsubstituted nitrogenated heterocyclic ring; R<1> represents a carboxyl group or a substituted or unsubstituted nitrogenated 5-membered heterocyclic ring; and R<2> and R<3> independently represent a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkylcarbonyl group.

Description

Drug for curing corneal and conjunctival disease
Technical field
The present invention relates to that xerophthalmia, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy (superficial punctate keratopathy), corneal epithelial defect, conjunctival epithelium are damaged, keratoconjunctivitis sicca, go up the therapeutic agent of wheel portion keratoconjunctivitis (superior limbickeratoconjunctivitis), filamentary keratitis cornea conjunctive disorders such as (Filamentary Keratitis), this therapeutic agent contains Biphenylmethyl derivant or its salt as effective ingredient.
Background technology
Cornea is transparent, the vesselless tissue of the about 1cm of diameter, the about 1mm of thickness, and in addition, conjunctiva is the eyeball surface at covering limbus of corneae rear and the mucosa at the eyelid back side.When known cornea or conjunctive disorder, visual function is produced material impact.By the cornea/conjunctive disorder that various diseases such as corneal ulcer, keratitis, conjunctivitis, xerophthalmia cause, corneal epithelial or conjunctival epithelium normally construct the generation harmful effect again, the result is sometimes even can injured corneas essence or the 26S Proteasome Structure and Function of endothelium.In recent years; Development along with cytobiology; Participate in cell division and move the factor that bonding stretches differentiation etc. and illustrated, existing report points out that the above-mentioned factor is being born important function (non-patent literature 1, non-patent literature 2) aspect the reparation of cornea/conjunctive disorder.
On the other hand; Existing report is pointed out; Biphenylmethyl derivant as effective ingredient of the present invention can suppress the Angiotensin II effect, as the therapeutic agent of cardiovascular diseases such as hypertension or heart failure useful (patent documentation 1, patent documentation 2, patent documentation 3 etc.).
But the above-mentioned Biphenylmethyl derivant of not relevant research does not have fully to hint that to ophthalmic, the particularly report of the pharmacological action of corneal conjunctive disorder the Biphenylmethyl derivant corneal conjunctive disorder with which kind of basic chemical structure is useful yet.
Patent documentation 1: No. 2709225 communique of patent
Patent documentation 2: No. 2868313 communique of patent
Patent documentation 3: special fair 5-29351 communique
Non-patent literature 1: face eye, 46,738-743 (1992)
Non-patent literature 2: ophthalmologic operation, 5,719-727 (1992)
Summary of the invention
Therefore, from above-mentioned numerous known Biphenylmethyl derivant, finding out as the useful chemical compound of drug for curing corneal and conjunctival disease, is an absorbing problem.
The concentrated on studies effect of in keratopathy treatment Biphenylmethyl derivant such as the inventor; The result finds; In the keratopathy curative effect test of using the keratopathy model; Biphenylmethyl derivant corneal pathological changes with specific basic chemical structure is brought into play the excellent effect of improving, thereby has accomplished the present invention.
That is, the present invention relates to
(1) a kind of drug for curing corneal and conjunctival disease contains the compound or its salt shown in the formula (1) as effective ingredient.
Figure S2006800132466D00021
(in the formula, X representes
Figure S2006800132466D00022
or
Ring Y representes to replace or do not have substituted nitrogen heterocyclic ring;
R 1The expression carboxyl, or replace or do not have substituted nitrogenous 5 yuan of heterocycles;
R 2And R 3Identical or different, expression hydrogen atom, replacement or do not have substituted alkyl, or replace or do not have a substituted alkyl carbonyl.)
(2) like (1) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00024
Ring Y representes
Figure S2006800132466D00025
or
Figure S2006800132466D00026
R 1The expression carboxyl,
Figure S2006800132466D00031
Or
R 4Expression hydrogen atom, hydroxyl, alkoxyl or alkyl;
R 5And R 6Can be identical or different, expression halogen atom, hydroxy alkyl or alkoxyalkyl;
R 7, R 8, R 9And R 10Identical or different, expression hydrogen atom, hydroxyl, alkoxyl or carboxyl or its ester.
(3) like (1) or (2) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00033
Ring Y representes
R 1The expression carboxyl or
Figure S2006800132466D00035
R 4Expression alkoxyl or alkyl;
R 5Expression halogen atom or hydroxy alkyl;
R 6Expression halogen atom, hydroxy alkyl or carboxyl or its ester.
(4) like (1) or (2) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00036
Ring Y representes
Figure S2006800132466D00037
R 1Expression
Figure S2006800132466D00038
R 4The expression alkyl.
(5) like (1) or (2) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00039
Ring Y representes
Figure S2006800132466D00041
R 1The expression carboxyl or
Figure S2006800132466D00042
R 4Expression alkoxyl or alkyl;
R 7Expression hydrogen atom or alkyl;
R 8The expression hydrogen atom;
R 9The expression hydrogen atom or
Figure S2006800132466D00043
R 10Expression hydrogen atom or carboxyl or its ester.
(6) like (3) or (5) described drug for curing corneal and conjunctival disease; Wherein, the ester of carboxyl is
Figure S2006800132466D00044
or
Figure S2006800132466D00045
(7) like (1) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00046
R 1Expression
Figure S2006800132466D00047
R 2And R 3Identical or different, expression hydrogen atom, carboxyalkyl or alkyl-carbonyl.
(8) like (1) or (7) described drug for curing corneal and conjunctival disease, in the general formula (1),
X representes
Figure S2006800132466D00048
R 1Expression
Figure S2006800132466D00049
R 2The expression carboxyalkyl;
R 3The expression alkyl-carbonyl.
(9) like (1) described drug for curing corneal and conjunctival disease; As effective ingredient; Contain 4 '-[[4-methyl-6-(1-tolimidazole-2-yl)-2-n-pro-pyl benzo imidazoles-1-yl] methyl]-1; 1 '-diphenyl-2-carboxylic acid, 2-normal-butyl-4-spiro cyclopentane-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-2-imidazoline-5-ketone, 2-butyl-4-chloro-5-hydroxymethyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl] imidazoles, 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid, 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate, N-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-N-valeryl-L-valine, 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid or (5-methyl-2-oxo-1; 3-dioxole-4-yl) salt of methyl 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid ester or above-claimed cpd.
(10) like each described therapeutic agent in (1)～(9); Wherein, said cornea/conjunctive disorder is that xerophthalmia, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, corneal epithelial defect, conjunctival epithelium are damaged, keratoconjunctivitis sicca, goes up wheel portion keratoconjunctivitis or filamentary keratitis.
(11) like each described drug for curing corneal and conjunctival disease in (1)～(10), its dosage form is eye drop or eye ointment.
Group to regulation in the Biphenylmethyl derivant with basic chemical structure shown in the above-mentioned general formula of the present invention (1) (below be called " this chemical compound ") is explained in further detail; Halogen is represented fluorine, chlorine, bromine or iodine; Alkyl representes that methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl etc. have the alkyl of the straight or branched of 1～6 carbon atom, and alkoxyl representes that methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, positive hexyloxy etc. have the alkoxyl of the straight or branched of 1～6 carbon atom.
Replace or do not have substituted nitrogen heterocyclic ring and represent to contain substituent nitrogen heterocyclic ring; As nitrogen heterocyclic ring; For example can enumerate pyridine, pyrimidine, pyrroles, imidazoles, pyrazoles, triazole, tetrazolium, triazine, tetrahydroquinoline, tetrahydroisoquinoline, indole, quinoline, phenanthridines, benzimidazole etc.; Replace or do not have substituted nitrogenous 5 yuan of heterocycles, for example can enumerate pyrroles, imidazoles, pyrazoles, triazole, tetrazolium, triazine etc. as nitrogenous 5 yuan of heterocycles for can contain substituent nitrogenous 5 yuan of heterocycles.
In addition, carboxyl ester is represented carboxyl and replacement or is not had substituted alkyl alcohol, replaces or do not have the ester that substituted aryl alcohol etc. forms.As the concrete example of alkylol, can enumerate methanol, ethanol, propanol, butanols etc., as the concrete example of aryl alcohol, can enumerate phenol, naphthols etc.
As R in the general formula [1] 1Preference, can enumerate carboxyl,
Figure S2006800132466D00061
As R 2And R 3Preference, can enumerate normal-butyl carbonyl, 1-carboxyl-2-methyl-propyl group,
As R 4Preference, can enumerate n-pro-pyl, normal-butyl, ethyoxyl,
As R 5Preference, can enumerate chlorine atom, 1-hydroxyl-1-Methylethyl,
As R 6Preference, can enumerate carboxyl, hydroxymethyl,
Figure S2006800132466D00062
As R 7Preference, can enumerate hydrogen atom, methyl,
As R 8Preference, can enumerate hydrogen atom,
As R 9Preference, can enumerate hydrogen atom,
Figure S2006800132466D00063
As R 10Preference, can enumerate hydrogen atom, carboxyl,
Figure S2006800132466D00064
Preferred concrete example as this chemical compound; For example can enumerate 4 '-[[4-methyl-6-(1-tolimidazole-2-yl)-2-n-pro-pyl benzo imidazoles-1-yl] methyl]-1; 1 '-diphenyl-2-carboxylic acid, 2-normal-butyl-4-spiro cyclopentane-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-2-imidazoline-5-ketone, 2-butyl-4-chloro-5-hydroxymethyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl] imidazoles, 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid, 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate, N-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-N-valeryl-L-valine, 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid, (5-methyl-2-oxo-1; 3-dioxole-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid ester, 2-ethyoxyl-1-[[2 '-(5-oxo-2H-1,2,4-oxadiazole-3-yl)-1; 1 '-biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, 2-butyl-4-chloro-1-[[2 '-(1 H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid etc.
The salt of this chemical compound so long as pharmaceutically acceptable salt get final product; There is not special limitation; Can enumerate sodium salt, potassium salt, lithium salts, calcium salt, magnesium salt; And the salt that forms with mineral acids such as hydrochloric acid, nitric acid, sulphuric acid, the salt that forms with organic acid such as acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid etc., quaternary ammonium salt is also included within the scope of salt of the present invention.More preferably sodium salt and potassium salt.Need to prove that this chemical compound also can form the form of hydrate and solvate.In addition, the optical isomer of this chemical compound, geometric isomer, tautomer, polymorphs body etc. are also included within the scope of the present invention.
This chemical compound can be based on the method manufacturing of following communique record, i.e. No. 2709225 communique of patent, No. 2868313 communique of patent, special fair 5-29351 communique, No. 2853611 communique of patent, No. 2514282 communique of patent, No. 2749458 communique of patent, special fair 7-25738 communique, No. 2645962 communique of patent, No. 3465215 communique of patent.
Among the present invention; Cornea/conjunctive disorder is meant the state that is caused cornea or conjunctival damage by a variety of causes, for example can enumerate that xerophthalmia, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, corneal epithelial defect, conjunctival epithelium are damaged, keratoconjunctivitis sicca, go up wheel portion keratoconjunctivitis, filamentary keratitis etc.
Drug for curing corneal and conjunctival disease of the present invention can be taken orally, also can non-oral administration.
As form of administration, can enumerate eye drop, eye ointment, injection, tablet, capsule, granule, powder etc., preferred especially eye drop.Can adopt common technology to process preparation.For example, eye drop can use following additives to prepare as required: isotonic agents such as sodium chloride, concentrated glycerin; Buffer agent such as sodium phosphate, sodium acetate; Surfactants such as polyoxyethylene sorbitan monooleate dehydration, polyoxyethylene stearate 40 esters, polyoxyethylene hydrogenated Oleum Ricini; Stabilizing agent such as sodium citrate, sodium ethylene diamine tetracetate; Antiseptic such as benzalkonium chloride, p-Hydroxybenzoate etc.PH is as long as in the scope that ophthalmic preparation allowed, preferably in 4～8 scope.
The eye ointment can use substrate commonly used such as white vaseline, liquid paraffin to modulate.In addition; Oral formulations such as tablet, capsule, granule, powder can use following additives to modulate as required: lactose, crystalline cellulose, starch, plant wet goods extender; Lubricant such as magnesium stearate, Talcum, binding agents such as hydroxypropyl cellulose, polyvinyl pyrrolidone, disintegrating agents such as carboxymethylcellulose calcium, low-substituted hydroxypropyl methylcellulose; Coating materials such as hypromellose, Polyethylene Glycol, silicones, gelatin liniment etc. such as film.
The invention still further relates to the cornea/conjunctive disorder Therapeutic Method of the compound or its salt shown in the general formula (1) of patient treatment effective dose.
The dosage of this chemical compound can suitably be selected according to symptom, age, dosage form etc., and eye drop can 1 time on the 1st～for several times, by the dosage eye drip administration of 0.00001～5% (w/v), preferred 0.001～3% (w/v).In addition, oral formulations, then usually can 1 time on the 1st or divide for several times, by the oral dose administration of 0.1～5000mg, preferred 1～1000mg.
Be described below; When implementing the curative effect test of keratopathy; The equal corneal pathological changes of this chemical compound model performance is good improves effect, therefore can effectively be used as the therapeutic agent of cornea conjunctive disorders such as xerophthalmia, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, corneal epithelial defect, conjunctival epithelium are damaged, keratoconjunctivitis sicca, last wheel portion keratoconjunctivitis, filamentary keratitis.
The specific embodiment
Provide the result and the formulation example of pharmacological testing below, above-mentioned example is used for understanding better the present invention, not delimit the scope of the invention.
[pharmacological testing]
The curative effect test of keratopathy
Use male SD rat, (Invest.Ophthalmol.Vis.Sci 42 (1): 96-100 (2001)), make the keratopathy model based on the method for Fujihara etc.After processing the keratopathy model, based on the first-class method in village (new ophthalmology 21 (1): 87-90 (2004)), the improvement rate of the keratopathy behind the eye drip is obtained in the judgement of marking of corneal pathological changes.
(experimental technique)
Use male SD rat, give pentobarbital sodium and implement general anesthesia, then, extract the outer lachrymal gland of eye socket, brought out keratopathy through 2 months.
Then; Be described below and give 4 '-[[4-methyl-6-(1-tolimidazole-2-yl)-2-n-pro-pyl benzo imidazoles-1-yl] methyl]-1; 1 '-diphenyl-2-carboxylic acid (below be called " compd A "), 2-normal-butyl-4-spiro cyclopentane-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-2-imidazoline-5-ketone (below be called " compd B "), 2-butyl-4-chloro-5-hydroxymethyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl] imidazoles one potassium salt (below be called " Compound C "), 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid (below be called " Compound D "), N-[[2 '-(1H-tetrazolium-5-yl)-1; 1 '-biphenyl-4-yl] methyl]-N-valeryl-L-valine (below be called " compd E ") and 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid monohydrate (below be called " compound F 17-hydroxy-corticosterone ").
Compd A eye drip group:
Splash into the normal saline that contains compd A (0.005%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
Compd B eye drip group:
Splash into the normal saline that contains compd B (0.04%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
Compound C eye drip group:
Splash into the normal saline that contains Compound C (0.5%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 3 rat, 6 eyes).
Compound D eye drip group:
Splash into the physiological phosphate buffer that contains Compound D (0.004%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
Compd E eye drip group:
Splash into the physiological phosphate buffer that contains compd E (0.004%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
Compound F 17-hydroxy-corticosterone eye drip group:
Splash into the physiological phosphate buffer that contains compound F 17-hydroxy-corticosterone (0.004%) at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
In addition, in the matched group, splash into normal saline or physiological phosphate buffer at two ophthalmic, 6 times on the 1st, eye drip 14 days (one group of 4 rat, 8 eyes).
After eye drip begins 14, with the lesion portion dyeing of fluorescein with cornea.By the fluorescent staining degree of top, middle part and the bottom of the corneal judgement of marking respectively of following benchmark, according to the improvement rate of the mean value calculation keratopathy of the mark summation of each part mentioned above.For normal eyes, calculate the meansigma methods of the mark summation of each part mentioned above.
(determinating reference)
0: be not colored
1: it is sparse to dye, and the coloured portions of each point-like separates
2: dye to moderate the coloured portions adjacency of a part of point-like
3: it is intensive to dye, the coloured portions adjacency of each point-like
(result)
Meansigma methods with the mark summation of matched group (normal saline or physiological phosphate buffer) is a benchmark (improvement rate: 0%), according to following calculating formula, calculate the improvement rate of compd A, B and C eye drip group respectively.The result is shown in table 1.According to identical method, obtain each improvement rate of Compound D and E eye drip group respectively, be shown in table 2, obtain the improvement rate of compound F 17-hydroxy-corticosterone eye drip group, be shown in table 3.Need to prove that fractional meansigma methods is the meansigma methods of 8 examples or 6 examples.
Improvement rate (%)={ (matched group)-(this chemical compound) }/pathological changes degree * 100
Pathological changes degree=(matched group)-(normal eyes)
[table 1]
Figure S2006800132466D00111
[table 2]
Figure S2006800132466D00112
[table 3]
Figure S2006800132466D00113
(discussion)
Shown in the result (table 1～3) of the pharmacological testing of above-mentioned use rat, compd A～F all significantly improves keratopathy.
[formulation example]
Provide the representative formulation example of use compd A～F below.
Prescription example 1
Among the 100ml
Compd A 10mg
Sodium chloride 900mg
Sterilization purification water is an amount of
Through changing the addition of compd A, can modulate concentration is the eye drop of 0.001% (w/v), 0.03% (w/v), 0.1% (w/v), 0.3% (w/v), 1.0% (w/v), 3.0% (w/v).
Prescription example 2
Among the 100ml
Compd B 50mg
Sodium chloride 800mg
Sodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate is an amount of
Sterilization purification water is an amount of
Through changing the addition of compd B, can modulate concentration is the eye drop of 0.002% (w/v), 0.01% (w/v), 0.25% (w/v), 1.25% (w/v), 3% (w/v).
Prescription example 3
Among the 100ml
Compound C 100mg
Sodium chloride 800mg
Sodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate is an amount of
Sterilization purification water is an amount of
Through changing the addition of Compound C, can modulate concentration is the eye drop of 0.003% (w/v), 0.01% (w/v), 0.03% (w/v), 0.05% (w/v), 0.3% (w/v), 1% (w/v), 3% (w/v).
Prescription example 4
Among the 100ml
Compound D 50mg
Sodium chloride 900mg
Sterilization purification water is an amount of
Through changing the addition of Compound D, can modulate concentration is the eye drop of 0.002% (w/v), 0.01% (w/v), 0.25% (w/v), 1.25% (w/v), 3% (w/v).
Prescription example 5
Among the 100ml
Compd E 100mg
Sodium chloride 800mg
Sodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate is an amount of
Sterilization purification water is an amount of
Through changing the addition of compd E, can modulate concentration is the eye drop of 0.003% (w/v), 0.01% (w/v), 0.03% (w/v), 0.05% (w/v), 0.3% (w/v), 1% (w/v), 3% (w/v).
Prescription example 6
Among the 100ml
Compound F 17-hydroxy-corticosterone 10mg
Sodium chloride 800mg
Sodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate is an amount of
Sterile purified water is an amount of
Through changing the addition of compound F 17-hydroxy-corticosterone, can modulate concentration is the eye drop of 0.001% (w/v), 0.03% (w/v), 0.1% (w/v), 0.3% (w/v), 1.0% (w/v), 3.0% (w/v).
Prescription example 7
Among the 100g
Compound C 0.3g
Liquid paraffin 10.0g
White vaseline is an amount of
Can modulate the eye ointment that concentration is 1% (w/w), 3% (w/w) through the addition that changes Compound C.
Prescription example 8
Among the 100g
Compound F 17-hydroxy-corticosterone 0.3g
Liquid paraffin 10.0g
White vaseline is an amount of
Can modulate the eye ointment that concentration is 1% (w/w), 3% (w/w) through the addition that changes compound F 17-hydroxy-corticosterone.

Claims (3)

1. the application of following compound or its salt in the preparation drug for curing corneal and conjunctival disease,
4 '-[[4-methyl-6-(1-tolimidazole-2-yl)-2-n-pro-pyl benzo imidazoles-1-yl] methyl]-1,1 '-diphenyl-2-carboxylic acid,
2-normal-butyl-4-spiro cyclopentane-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-2-imidazoline-5-ketone,
2-butyl-4-chloro-5-hydroxymethyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazoles,
2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid,
1-(cyclohexyl oxygen base ketonic oxygen base) ethyl 2-ethyoxyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate,
N-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl]-N-valeryl-L-valine,
4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid,
Or the salt of (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-n-pro-pyl-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-biphenyl-4-yl] methyl] imidazole-5-carboxylic acid ester or these chemical compounds.
2. application as claimed in claim 1; Wherein, said cornea/conjunctive disorder is that xerophthalmia, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, corneal epithelial defect, conjunctival epithelium are damaged, keratoconjunctivitis sicca, goes up wheel portion keratoconjunctivitis or filamentary keratitis.
3. application as claimed in claim 1, wherein, dosage form is eye drop or eye ointment.
CN2006800132466A 2005-04-21 2006-04-21 Drug for curing corneal and conjunctival disease Expired - Fee Related CN101163474B (en)

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EP1872783B1 (en) 2011-12-28
EP1872783A1 (en) 2008-01-02
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KR20070121791A (en) 2007-12-27
PL1872783T3 (en) 2012-05-31
RU2420280C2 (en) 2011-06-10
CN101163474A (en) 2008-04-16
US20090042962A1 (en) 2009-02-12
NO20075980L (en) 2008-01-17
ES2379580T3 (en) 2012-04-27
PT1872783E (en) 2012-01-16

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